Glp1 pharmaceutical compositions

Abstract

The present invention relates to an oral capsule composition comprising 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and a pH modifier.

1 . An oral capsule composition comprising
 a spray dried dispersion (SDD) of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; and   a pH modifier selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and a mixture thereof.   
     
     
         2 . (canceled) 
     
     
         3 . The composition as claimed by  claim 1  wherein the pH modifier is selected from the group consisting of calcium carbonate, anhydrous calcium carbonate, sodium bicarbonate, anhydrous sodium bicarbonate, sodium carbonate, anhydrous sodium carbonate, magnesium hydroxide, and anhydrous magnesium hydroxide. 
     
     
         4 . (canceled) 
     
     
         5 . The composition as claimed by claim  2 , wherein the pH modifier is sodium bicarbonate. 
     
     
         6 . The composition as claimed by  claim 5 , wherein the pH modifier is anhydrous sodium bicarbonate. 
     
     
         7 . (canceled) 
     
     
         8 . The composition as claimed by any one of  claims 1, 3 and 5 to 6 , wherein the 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, is
 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5 Ca hydrate.   
     
     
         9 . The composition as claimed by  claim 8 , wherein the 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, is
 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5 Ca hydrate in an amount of between about 1.2 to about 46 mg, on a free acid basis, per capsule composition.   
     
     
         10 . (canceled) 
     
     
         11 . The composition as claimed by any one of  claims 1, 3 and 5 to 6 , wherein the 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof, is in an amount of between about 1 mg to about 45 mg, on a free acid basis, per capsule. 
     
     
         12 - 14 . (canceled) 
     
     
         15 . A composition comprising:
 an SDD of about 30 wt % to about 35 wt % of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; in an amount of between about 0.7 mg to about 50 mg, on a free acid basis; and the balance of the SDD is composed of PVP-VA; and   a pH modifier selected from the group consisting of calcium carbonate, magnesium carbonate, sodium bicarbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, magnesium oxide, and a mixture thereof.   
     
     
         16 . The composition as claimed by  claim 15 , wherein the composition comprises:
 the SDD of about 30 wt % 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a pharmaceutically acceptable salt thereof; in an amount of between about 0.7 mg to about 45 mg, on a free acid basis;   a pH modifier which is sodium bicarbonate; in an amount of about 150 mg to about 650 mg;   optionally, a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof; in an amount of about 0 mg to about 200 mg; and   optionally, a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof; in an amount of about 0 mg to about −20 mg.   
     
     
         17 . The composition as claimed by  claim 16 , wherein the composition comprises:
 an SDD of about 30 wt % of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of between about 1 mg to about 36 mg, on a free acid basis; and the balance of the SDD is composed of PVP-VA;   a pH modifier which is sodium bicarbonate; in an amount of about 200 mg to about 600 mg;   optionally, a filler selected from the group consisting of a sugar alcohol, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, starch, dicalcium phosphate, and a mixture thereof; in an amount of about 0 mg to about 60 mg; and   optionally, a glidant selected from the group consisting of silicon oil, silicon dioxide, talc, magnesium carbonate, and a mixture thereof; in an amount of about 0 mg to about −20 mg.   
     
     
         18 . (canceled) 
     
     
         19 . The composition as claimed by  claim 17 , wherein:
 no filler is present; and   the glidant is silicon oil; in an amount of about 0.1 mg to about 5 mg.   
     
     
         20 . The composition as claimed by any one of  claims 15-17 and 19 , wherein the SDD has a mean particle size of about 5 μm to about 113 μm in diameter. 
     
     
         21 . The composition as claimed by  claim 17 , wherein the composition comprises:
 an SDD of about 30 wt % of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 1 mg, on a free acid basis;   a pH modifier which is sodium bicarbonate; in an amount of about 200 mg;   a filler which is MCC PH-102; in an amount of about 40 mg to about 50 mg; and   a glidant which is silicon oil or silicon dioxide; in an amount of about 1 mg to about 5 mg   wherein the total weight of the composition is about 250 mg.   
     
     
         22 . The composition as claimed by  claim 17 , wherein the composition comprises:
 an SDD of about 30 wt % of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 16 mg, on a free acid basis;   a pH modifier which is sodium bicarbonate; in an amount of about 200 mg;   a filler which is MCC PH-102; in an amount of about 5 mg to about 10 mg; and   a glidant which is silicon oil or silicon dioxide; in an amount of about 1 mg to about 5 mg   wherein the total weight of the composition is about 260 mg.   
     
     
         23 . The composition as claimed by  claim 17 , wherein the composition comprises:
 an SDD of about 30 wt % of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 6 mg, on a free acid basis; and about 70 wt % of PVP-VA in an amount of about 14 mg;   a pH modifier which is sodium bicarbonate; in an amount of about 600 mg; and   a glidant which is silicon oil; in an amount of about 1 mg to about 10 mg.   
     
     
         24 . The composition as claimed by  claim 17 , wherein the composition comprises:
 an SDD of about 30 wt % of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 12 mg, on a free acid basis; and about 70 wt % of PVP-VA in an amount of about 28 mg;   a pH modifier which is sodium bicarbonate; in an amount of about 600 mg; and   a glidant which is silicon oil; in an amount of about 1 mg to about 10 mg.   
     
     
         25 . The composition as claimed by  claim 17 , wherein the composition comprises:
 an SDD of about 30 wt % of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, 0.5 Ca hydrate; in an amount of about 36 mg, on a free acid basis; and about 70 wt % of PVP-VA in an amount of about 83 mg;   a pH modifier which is sodium bicarbonate; in an amount of about 600 mg; and   a glidant which is silicon oil; in an amount of about 1 mg to about 10 mg.   
     
     
         26 . The composition as claimed by any one of  claims 21-25 , wherein the SDD has a mean particle size of about 5 μm to about 113 μm in diameter. 
     
     
         27 . The composition as claimed by  claim 26 , wherein the SDD has a mean particle size of about 40 μm to about 65 μm in diameter. 
     
     
         28 . The composition as claimed by  claim 27 , wherein the composition is in a capsule shell. 
     
     
         29 . (canceled)